Leukocytes and complement are important components of the inflammatory reaction. Evidence exists that the lung may be subject to complement-induced injury by either (1) intrapulmonary complement activation leading to migration of leukocytes into the lung, or by (2) intravascular complement activation leading to sequestration of neutrophils in the pulmonary vasculature. We have studied an animal model of pulmonary inflammation using C5 deficient mice, and found that in an intrapulmonary location, C5 may play a central role in the induction of pulmonary inflammation. In addition, highly purified C5a des Arg has been found to be more inflammatory than C5a when instilled in rabbit lungs. Pulmonary injury after intravascular complement activation was recently reported in uremic patients undergoing hemodialysis. Investigation of this process led to the hypothesis that the C5 molecule was central to the reported changes. In particular, the anaphylatoxin C5a was felt to be pathogenic during dialysis and in adult respiratory distress syndrome by causing neutrophil sequestration in pulmonary vessels. This proposal seeks to study interactions of intravascular complement, leukocytes, and the lung to determine (1) which O5 fragment C5a or C5a des Arg, is primarily responsible for changing circulating leukocyte patterns, (2) how are C5a and C5a des Arg cleared from the body, (3) what are the structural (histologic) and functional (physiologic) alterations produced in the lung by intravascular complement activation and/or pulmonary sequestration of neutrophils, and (4) will other stimuli, such as those that might generate intrapulmonary chemotactic factors, increase the injury seen with intravascular complement activation? Studies to address these questions will be done in vivo using the rabbit. Injury will be assessed structurally by light and electron microscopy, and will be quantitated by measuring permeability, hemorrhage, and neutrophil and monocyte accumulation. Functionally, changes will be monitored with arterial blood gases and with continuous measurements of pulmonary mechanics. The study is designed to further define the potential for production of pulmonary injury by intravascular complement activation.